2-substituted estra-1,3,5(10)-trien-17-ones as inhibitors of 17β-hydroxy steroid dehydrogenase type 1

Abstract

The invention relates to new 2-substituted estra-1,3,5(10)-trien-17-ones of formula I as well as their pharmaceutically acceptable salts, their methods of manufacture and use as medicaments for prophylaxis and/or therapy of estrogen-dependent diseases that can be influenced by the inhibition of 17beta-hydroxy steroid dehydrogenase type 1.

The invention claimed is: 
     
       1. A 2-substituted estra-1,3,5(10)-trien-17-one compound of formula I 
       
         
           
           
               
               
           
         
       
       in which
 R 2  means phenylethyl, phenylpropyl or phenylethinyl, 
 R 13  means a hydrogen atom or a methyl group, 
 R 16  means a hydrogen atom or a fluorine atom, 
 Z means an oxygen atom or a sulfur atom, 
 R 3  and R 5  mean, in each case independently of one another, an α- or β-position hydrogen atom, 
 R 4  and R 6  mean, in each case independently of one another, an α- or β-position hydrogen atom, a C 1 -C 5 -alkyl group, a C 1 -C 5 -alkyloxy group, a C 1 -C 5 -acyl group, a hydroxy group, an aralkyl or heteroaralkyl radical, or an alkylaryl or alkylheteroaryl radical, 
 R 3  and R 4  together can also be an oxygen atom, 
 R 5  and R 6  together can also be an oxygen atom, 
 R 7  and R 8  in each case mean a hydrogen atom or together a CH 2  group, 
 wherein the aryl or heteroaryl groups are unsubstituted or substituted by methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifiuoromethylthio, methoxy, ethoxy, nitro, cyano, halogen, hydroxy, amino, mono(C 1-8 -alkyl)amino, di(C 1-8 -alkyl)amino wherein the alkyl groups are identical or different, or di(aralkyl)amino wherein the aralkyl groups are identical or different, and 
 wherein the dotted lines in the B-, C- and D-ring of the steroid skeleton additionally can be up to two double bonds, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       2. A compound according to  claim 1 , wherein R 2  is phenylethyl, or phenylpropyl. 
     
     
       3. A compound according to  claim 1 , wherein R 13  is a hydrogen atom. 
     
     
       4. A compound according to  claim 1 , wherein R 2  is a phenylethinyl group. 
     
     
       5. A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       6. A pharmaceutical composition according to  claim 5 , further comprising at least one other active ingredient. 
     
     
       7. A pharmaceutical composition according to  claim 6 , wherein the at least one other active ingredient is an antiandrogen, antigestagen, aromatase inhibitor or an antiestrogen. 
     
     
       8. A 2-substiftited estra-1,3,5(10)-trien-17-one compound of formula I 
       
         
           
           
               
               
           
         
       
       in which
 R 2  means a C 1 -C 5 -alkyloxy group, an aralkyl or heteroaralkyl radical, an alkylaryl or alkyiheteroaryl radical, a radical —O—C n F m H o , a group CH 2 XY, a phenylethinyl group, a chlorine, iodine, or bromine atom or a nitrile group, 
 n is 1, 2, 3, 4, 5 or 6, 
 m is≧1, 
 m+o is=2n=1, 
 X is an oxygen atom, 
 Y is an alkyl radical with 1 to 4 carbon atoms, 
 R 13  means a hydrogen atom or a methyl group, 
 R 16  means a fluorine atom, 
 Z means an oxygen atom or a sulfur atom, 
 R 3  and R 5  mean, in each case independently of one another, an α- or β-position hydrogen atom, 
 R 4  and R 6  mean, in each case independently of one another, an α- or β-position hydrogen atom, a C 1 -C 5 -alkyl group, a C 1 -C 5 -alkyloxy group, a C 1 -C 5 -acyl group, a hydroxy group, an aralkyl or heteroaralkyl radical, or an alkylaryl or alkylheteroaryl radical, 
 R 3  and R 4  together can also be an oxygen atom, 
 R 5  and R 6  together can also be an oxygen atom, 
 R 7  and R 8  in each case mean a hydrogen atom or together a CH 2  group, 
 wherein the aryl or heteroaryl groups are unsubstituted or substituted by methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen, hydroxy, amino, mono(C 1-8 -alkyl)amino, di(C 1-8 -alkyl)amino wherein the alkyl groups are identical or different, or di(aralkyl)amino wherein the aralkyl groups are identical or different, and 
 wherein the dotted lines in the B-, C- and D-ring of the steroid skeleton additionally can be up to two double bonds, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       9. A compound according to  claim 8 , wherein R 2  is a C 4 -C 5 -alkyloxy group, an arallcyl or an alkylaryl radical, a radical —O—C n F m H o , a group CH 2 XY, or a phenylethinyl group. 
     
     
       10. A compound according to  claim 8 , wherein R 2  is a chlorine atom. 
     
     
       11. A compound according to  claim 8 , wherein R 2  is a C 1 -C 5 -alkyloxy group, an aralkyl or heteroaralkyl radical, an alkylaryl or alkyiheteroaryl radical, a radical —O—C n F m H o , a group CH 2 XY, a phenylethinyl group, or a nitrile group. 
     
     
       12. A compound according to  claim 10 , wherein R 13  is a hydrogen atom. 
     
     
       13. A compound according to  claim 8 , wherein R 2  is an aralkyl or heteroaralkyl radical, an alkylaryl or alkyiheteroaryl radical, a radical —O—C n F m H o , a group CH 2 XY, a phenylethinyl group, a chlorine, iodine, or bromine atom or a nitrile group. 
     
     
       14. A 2-substituted estra-1,3,5 (10)-trien-17-one compound of formula I 
       
         
           
           
               
               
           
         
       
       in which
 R 2  means a C 1 -C 5 -alkyloxy group, an aralkyl or heteroaralkyl radical, an alkylaryl or alkyiheteroaryl radical, a radical —O—-C n F m H o , a group CH 2 XY, a phenylethinyl group, a halogen atom, or a nitrile group, 
 n is 1, 2, 3, 4, 5 or 6, 
 m is≧1, 
 m+o is=2n=1, 
 X is an oxygen atom, 
 Y is an alkyl radical with 1 to 4 carbon atoms, 
 R 13  means a hydrogen atom or a methyl group, 
 R 16  means a fluorine atom, 
 Z means an oxygen atom or a sulfur atom, 
 R 3  and R 5  mean, in each case independently of one another, an α- or β-position hydrogen atom, 
 R 4  and R 6  mean, in each case independently of one another, an α- or β-position hydrogen atom, a C 1 -C 5 -alkyl group, a C 1 -C 5 -alkyloxy group, a C 1 -C 5 -acyl group, a hydroxy group, an aralkyl or heteroaralkyl radical, or an alkylaryl or alkylheteroaryl radical, 
 R 3  and R 4  together can also be an oxygen atom, 
 R 5  and R 6  together can also be an oxygen atom, 
 R 7  and R 8  in each case mean a hydrogen atom or together a CH 2  group, 
 wherein the aryl or heteroaryl groups are unsubstituted or substituted by methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen, hydroxy, amino, mono(C 1-8 -alkyl)amino, di(C 1-8 -alkyl)amino wherein the alkyl groups are identical or different, or di(aralkyl)amino wherein the aralkyl groups are identical or different, and 
 wherein the dotted lines in the B-, C- and D-ring of the steroid skeleton additionally can be up to two double bonds, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       15. A compound according to  claim 14 , wherein R 2  is a C 4 -C 5 -alkyloxy group, an aralkyl or an alkylaryl radical, a radical —O—C n F m H o , a group CH 2 XY, or a phenylethinyl group. 
     
     
       16. A 2-substituted estra-1,3,5(10)-trien-17-one compound of formula I 
       
         
           
           
               
               
           
         
       
       in which
 R 2  means a C 1 -C 5 -alkyloxy group, an aralkyl or heteroaralkyl radical, an alkylaryl or alkyiheteroaryl radical, a radical —O—C n F m H o , a group CH 2 XY, a phenylethinyl group, a halogen atom, or a nitrile group, 
 n is 1, 2, 3, 4, 5 or 6, 
 m is≧1, 
 m+o is=2n=1, 
 X is an oxygen atom, 
 Y is an alkyl radical with 1 to 4 carbon atoms, 
 R 13  means a hydrogen atom or a methyl group, 
 R 16  means a fluorine atom, 
 Z means an oxygen atom or a sulfur atom, 
 R 3  and R 5  mean, in each case independently of one another, an α- or β-position hydrogen atom, 
 R 4  and R 6  mean, in each case independently of one another, an α- or β-position hydrogen atom, a C 1 -C 5 -alkyl group, a C 1 -C 5 -alkyloxy group, a C 1 -C 5 -acyl group, a hydroxy group, an aralkyl or heteroaralkyl radical, or an alkylaryl or alkylheteroaryl radical, 
 R 7  and R 8  in each case mean a hydrogen atom or together a CH 2  group, 
 wherein the aryl or heteroaryl groups are unsubstituted or substituted by methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen, hydroxy, amino, mono(C 1-8 -alkyl)amino, di(C 1-8 -alkyl)amino wherein the alkyl groups are identical or different, or di(aralkyl)amino wherein the aralkyl groups are identical or different, and 
 wherein the dotted lines in the B-, C- and D-ring of the steroid skeleton additionally can be up to two double bonds, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       17. A compound according to  claim 16 , wherein R 2  is a C 4 -C 5 -alkyloxy group, an aralkyl or an alkylaryl radical, a radical —O—C n F m H o , a group CH 2 XY, or a phenylethinyl group. 
     
     
       18. A compound according to  claim 16 , wherein R 2  is an aralkyl or an alkylaryl radical, a radical —O—C n F m H o , a group CH 2 XY, or a phenylethinyl group. 
     
     
       19. A method for the therapy of hormone-dependent tumor disease of a male or female reproductive gland, male or female sex organ, or a mammary gland comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to  claim 5 . 
     
     
       20. A method for the therapy of breast cancer comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to  claim 5 . 
     
     
       21. A method for the therapy of prostate cancer comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to  claim 5 . 
     
     
       22. A method for treating endometriosis comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to  claim 5 . 
     
     
       23. A method of treating breast cancer, prostate cancer, or endometriosis comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       24. A method of treating breast cancer, prostate cancer, or endometriosis comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound according to  claim 8  and a pharmaceutically acceptable carrier. 
     
     
       25. A method of treating breast cancer, prostate cancer, or endometriosis comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound according to  claim 14  and a pharmaceutically acceptable carrier. 
     
     
       26. A method of treating breast cancer, prostate cancer, or endometriosis comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound according to  claim 16  and a pharmaceutically acceptable carrier.